This proposal is concerned with defining the relationship between bone resorption and DNA synthesis. Our understanding of the mechanisms by which hormones and local regulators of bone resorption alter function in bone resorbing cells is limited. The osteoclast which is believed to be the principal cell responsible for bone resorption does not undergo cell division. Instead, increases in osteoclast number are dependent on the availability of a mononuclear precursor cell which is incorporated into osteoclasts. Parathyroid hormone (PTH), a potent stimulator of resorption, affects osteoclasts by increasing their number and activating their resorptive mechanisms. PTH also increases cell replication in mononuclear cells in bone. Recently, using inhibitors of DNA synthesis, I have found that in fetal rat bone cultures PTH can increase osteoclast number and stimulate bone resorption when cell replication is markedly inhibited, and that epidermal growth factor (EGF), a potent mitogen in this culture system, does require DNA synthesis to produce a resorptive effect. The goals of this study are to determine if other stimulators of bone resorption require DNA synthesis and if the various components of the resorptive response are affected equally by inhibitors of DNA synthesis. I will also examine "escape" from calcitonin to see if this phenomenon requires cell replication and I will determine if EGF can increase replication in osteoclast precursors and synergistically enhance resorption with PTH. Finally, I will try to develop an in vivo model of bone resorption to determine if my in vitro work can be extended to this system. In these experiments the response of bones will be measured as calcium release, matrix degradation, lysosomal enzyme and collagenase release and as cyclic AMP concentrations in bone. Inhibition of cell replication will be produced with agents such as hydroxyurea and quantitated by measuring (3H)thymidine incorporation into bone, mitotic index and cytofluorimetry.